A prospective randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma.
Authors: John Paul Y.C. Shen, Abdelrahman M.G. Yousef, Fadl A. Zeineddine, Mohammad A. Zeineddine, Karen A. Beaty, Lisa Scofield, Rebecca Slack Tidwell, Safia Rafeeq, Nicholas James Hornstein, Elizabeth A Lano, Cathy Eng, Aurelio Matamoros, Wai Chin Foo, Abhineet Uppal, Christopher Scally, Paul F. Mansfield, Melissa Taggart, Kanwal Pratap Singh Raghav, Michael J. Overman, Keith F. Fournier
Journal: Journal of Clinical Oncology (2023)

163 Background: Appendiceal adenocarcinoma is both a rare and heterogenous tumor, with marked contrast in the natural history of low-grade and high-grade tumors (5-year OS 68% for low-grade vs. 7% for high-grade). While low-grade appendiceal adenocarcinoma is primarily treated with surgical resection sometimes followed by hyperthermic intraperitoneal chemotherapy (HIPEC), many inoperable candidates are treated with systemic chemotherapy although there is no prospective data supporting this practice. The purpose of our study was to objectively evaluate the effectiveness of systemic chemotherapy in low-grade mucinous appendiceal adenocarcinoma. Methods: A randomized crossover trial of surgically unresectable low-grade (well differentiated) mucinous appendiceal adenocarcinoma was performed with patients randomized to either 6 months observation followed by 6 months of chemotherapy (physician’s choice), or initial chemotherapy followed by observation. In this way each patient would serve as their own control. Enrollment of 30 patients was planned to have complete 6- and 12-month tumor measurements for 24 patients, providing 80% power at 0.05 significance level to detect a 5.0% difference in change in tumor size as measured by peritoneal RECIST in observation vs. treatment periods. Results: The trial closed early due to slow accrual. A total of 24 patients were enrolled. The majority of patients were treated with either 5FU or capecitabine (n = 15, 63%), bevacizumab was added for 3 (13%), and 3 were treated with doublet chemotherapy (FOLFOX/FOLFIRI). 15 patients who completed both treatment and observation periods were available for the primary analysis, the mean difference in tumor size was -4.5% (95% CI: -12.6, 3.7), indicating a slight trend towards faster growth on treatment than observation. This difference was not statistically or clinically significant (8.4% growth on treatment vs. 4.0% observation, p=0.26). Of the 18 patients who received any chemotherapy during the study period, zero achieved an objective response, 14 (77.8%) had stable disease during the entire year of follow up, and 4 (12.2%) had progression on study. Patient reported quality of life metrics identified that fatigue (p=0.02), peripheral neuropathy (p=0.014), and financial difficulty (p=0.0013) were all significantly worse while on treatment. There was not a significant difference in rate of bowel obstruction between the treatment first vs. observation first arms (12.5%, (n=3) vs 8.3%, (n=2)). Conclusions: These data from a prospective, randomized crossover trial indicate that patients with low-grade mucinous appendiceal adenocarcinoma do not derive benefit from 5FU based chemotherapy but do incur toxicity. These data further highlight the unique biology of low-grade appendiceal cancer and demonstrates the need to identify novel systemic therapies for this patient population. Clinical trial information: NCT01946854 .